Endometriosis is a complex disorder associated with pelvic pain and infertility, and is characterized by the implantation of endometrial tissue outside the uterus, primarily on the pelvic peritoneum and ovaries (Giudice L C, Kao L C (2004) The Lancet 364:1789-99). Endometriosis affects 6-10% of women in the general population and 35-50% of women with pain and/or infertility (Eskenazi B, Warner M L (1997) Obstet Gynecol Clin North Am 24:235-58). It is widely accepted that by retrograde menstruation (Sampson J A (1927) Am J Obstet Gynecol 14:442-469), endometrial tissue establishes itself on the peritoneum of women with endometriosis due to heritable and/or acquired defects that confer survival advantage and promote attachment, growth, neoangiogenesis, and invasion into the peritoneum.
The main clinical symptoms of endometriosis are pelvic pain, bleeding and infertility, with the latter proposed to be related to impaired implantation due, in part, to impaired decidualization of endometrial stromal fibroblasts (ESFs). Progesterone and cyclic AMP (cAMP) are important in ESF decidualization and stimulate insulin growth factor binding protein 1 (IGFBP-1) and prolactin (PRL), markers of decidualization. Clinical observations suggest the presence of progesterone (P4) resistance in some women with endometriosis. In addition, endometriotic lesions synthesize aromatase, a key enzyme in the biosynthesis of E2, a potential regulator of lesion growth and pain.
Though the estrogen dependence of endometriosis is well established, the role of progesterone in this disorder is comparatively less well developed. The relative balance of progesterone and estrogen steroidal activity governs the function of normal endometrium throughout the menstrual cycle. The growth promoting effects of estrogen during the proliferative phase of the cycle are countered by progesterone's anti-proliferative actions at the post-ovulatory onset of the secretory phase and decidualizing effects on endometrial stroma later in the secretory phase (Ferenczy A et al. (1979) Am J Obstet Gynecol 133:859-67; Felix J C, Farahmand S (1997) Contraception 55:19-22). A phenotype of attenuated progesterone response is suggested in endometriosis, and interestingly, progestin-based treatment of pain associated with this disorder is variably effective (Winkel C A, Scialli A R (2001) J Womens Health Gend Based Med 10:137-62; Metzger D A et al. (1988) Hum Pathol 19:1417-24).
The dysregulation of various progesterone target genes during the implantation window in women with endometriosis have been reported (Kao L C et al. 2003 Endocrinology 144:2870-81; Kamat A A et al. (2004) Fertil Steril 82:1681-3; Lessey B A et al. (1994) J Clin Endocrinol Metab 79:643-9; Lessey B A et al (1992) J Clin Invest 90:188-95; Cullinan E B et al. (1996) Proc Natl Acad Sci 93:3115-20; Taylor H S et al. (1999) Hum Reprod 14:1328-31). An endometrial microenvironment characterized by attenuated progesterone response may be inhospitable to embryonic implantation. Reduced responsiveness, or resistance, to progesterone in eutopic endometrium has been implicated in the pathophysiology of this enigmatic condition, as suggested by the altered pattern of matrix metalloproteinase (MMP) gene expression in the secretory phase (Osteen K G et al. (2005) Fertil Steril 83:529-37). Interestingly, in vitro treatment of endometrial tissues acquired from women with endometriosis with progesterone fails to fully suppress either pro-MMP-3 or pro-MMP-7 secretion and fails to prevent the ability of these tissues to establish experimental disease in mice (Bruner-Tran K L et al. (2002) J Clin Endocrinol Metab 87:4782-91). More recently, endometrial cell culture and nude mouse models were used to demonstrate that progesterone insensitivity was intrinsic to the eutopic endometrium of women with endometriosis and could be corrected by treatment with the synthetic progestin, tanaproget (Bruner-Tran K L et al. (2006) J Clin Endocrinol Metab 91:1554-60).
Progesterone resistance may occur at the level of the progesterone receptor isoforms (PR-A and PR-B) (Igarashi T M et al. (2005) Fertil Steril 84:67-74; Attia G R et al. (2000) J Clin Endocrinol Metab 85:2897-902), steroid receptor co-activators, or down-stream effectors (TGFβ, DKK-1, Retinoic acid, c-myc, etc). In endometriotic lesions, a decrease in the expression of the progesterone target gene, 17-beta hydroxysteroid dehydrogenase type I, is evidence of progesterone resistance in ectopic endometrium (Vierikko P et al. (1985) Fertil Steril 43:218-24, Bulun S E et al. (2006) Mol Cell Endocrinol 248:94-103).
There is a need in the art for the identification of molecular differences in the endometrium of women with endometriosis in order to better understand the pathogenesis of this condition and to facilitate development of novel strategies for the treatment of associated infertility and pain. The present invention fulfills this need by identifying biomarkers and kits useful in the diagnosis and prognosis of endometriosis and infertility in women with endometriosis, presenting methods for identifying compounds for treating or preventing endometriosis and infertility caused by endometriosis, and by presenting therapeutics useful in the treatment or prevention of endometriosis and infertility caused by endometriosis, among other embodiments.